TY - JOUR
T1 - Phase I study of DNX-2401 (delta-24-RGD) oncolytic adenovirus
T2 - replication and immunotherapeutic effects in recurrent malignant glioma
AU - Lang, Frederick F.
AU - Conrad, Charles
AU - Gomez-Manzano, Candelaria
AU - Alfred Yung, W. K.
AU - Sawaya, Raymond
AU - Weinberg, Jeffrey S.
AU - Prabhu, Sujit S.
AU - Rao, Ganesh
AU - Fuller, Gregory N.
AU - Aldape, Kenneth D.
AU - Gumin, Joy
AU - Vence, Luis M.
AU - Wistuba, Ignacio
AU - Rodriguez-Canales, Jaime
AU - Villalobos, Pamela A.
AU - Dirven, Clemens M.F.
AU - Tejada, Sonia
AU - Valle, Ricardo D.
AU - Alonso, Marta M.
AU - Ewald, Brett
AU - Peterkin, Joanna J.
AU - Tufaro, Frank
AU - Fueyo, Juan
N1 - Publisher Copyright:
© 2018 by American Society of Clinical Oncology.
PY - 2018/5/10
Y1 - 2018/5/10
N2 - Purpose DNX-2401 (Delta-24-RGD; tasadenoturev) is a tumor-selective, replication-competent oncolytic adenovirus. Preclinical studies demonstrated antiglioma efficacy, but the effects and mechanisms of action have not been evaluated in patients. Methods A phase I, dose-escalation, biologic-end-point clinical trial of DNX-2401 was conducted in 37 patients with recurrent malignant glioma. Patients received a single intratumoral injection of DNX-2401 into biopsy-confirmed recurrent tumor to evaluate safety and response across eight dose levels (group A). To investigate the mechanism of action, a second group of patients (group B) underwent intratumoral injection through a permanently implanted catheter, followed 14 days later by en bloc resection to acquire post-treatment specimens. Results In group A (n = 25), 20% of patients survived . 3 years from treatment, and three patients had a $ 95% reduction in the enhancing tumor (12%), with all three of these dramatic responses resulting in . 3 years of progression-free survival from the time of treatment. Analyses of post-treatment surgical specimens (group B, n = 12) showed that DNX-2401 replicates and spreads within the tumor, documenting direct virus-induced oncolysis in patients. In addition to radiographic signs of inflammation, histopathologic examination of immune markers in post-treatment specimens showed tumor infiltration by CD8 + and T-bet + cells, and transmembrane immunoglobulin mucin-3 downregulation after treatment. Analyses of patient-derived cell lines for damage-associated molecular patterns revealed induction of immunogenic cell death in tumor cells after DNX-2401 administration. Conclusion Treatment with DNX-2401 resulted in dramatic responses with long-term survival in recurrent high-grade gliomas that are probably due to direct oncolytic effects of the virus followed by elicitation of an immune-mediated antiglioma response.
AB - Purpose DNX-2401 (Delta-24-RGD; tasadenoturev) is a tumor-selective, replication-competent oncolytic adenovirus. Preclinical studies demonstrated antiglioma efficacy, but the effects and mechanisms of action have not been evaluated in patients. Methods A phase I, dose-escalation, biologic-end-point clinical trial of DNX-2401 was conducted in 37 patients with recurrent malignant glioma. Patients received a single intratumoral injection of DNX-2401 into biopsy-confirmed recurrent tumor to evaluate safety and response across eight dose levels (group A). To investigate the mechanism of action, a second group of patients (group B) underwent intratumoral injection through a permanently implanted catheter, followed 14 days later by en bloc resection to acquire post-treatment specimens. Results In group A (n = 25), 20% of patients survived . 3 years from treatment, and three patients had a $ 95% reduction in the enhancing tumor (12%), with all three of these dramatic responses resulting in . 3 years of progression-free survival from the time of treatment. Analyses of post-treatment surgical specimens (group B, n = 12) showed that DNX-2401 replicates and spreads within the tumor, documenting direct virus-induced oncolysis in patients. In addition to radiographic signs of inflammation, histopathologic examination of immune markers in post-treatment specimens showed tumor infiltration by CD8 + and T-bet + cells, and transmembrane immunoglobulin mucin-3 downregulation after treatment. Analyses of patient-derived cell lines for damage-associated molecular patterns revealed induction of immunogenic cell death in tumor cells after DNX-2401 administration. Conclusion Treatment with DNX-2401 resulted in dramatic responses with long-term survival in recurrent high-grade gliomas that are probably due to direct oncolytic effects of the virus followed by elicitation of an immune-mediated antiglioma response.
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U2 - 10.1200/JCO.2017.75.8219
DO - 10.1200/JCO.2017.75.8219
M3 - Article
C2 - 29432077
AN - SCOPUS:85043530708
SN - 0732-183X
VL - 36
SP - 1419
EP - 1427
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 14
ER -